Bradykinin (BK) belongs to kinins and forms, together with kallidin and T-kinin, the sub-group of kinins present in mammals. Kinins play an important role as mediators of pain and inflammation, both in the central and peripheral nervous system. Bradykinin is, in particular, a nonapeptide produced by the body in physiopathological conditions.
Two types of kinins receptors exist, B1 and B2. The main characteristic of the B1 receptor is that it is more inducible than constitutive. It is expressed in tissues in inflammation or stress conditions. On the other hand, B2 is a constitutive receptor normally present in all tissues and acts a mediator during the inflammatory processes. Bradykinin and kallidin are released from their protein precursors (known as kininogens), by proteolytic enzymes named kininogenases. Among these, the main role is played by kallikreins which however, once released by the precursor, can exert their action only for a short time as they are quickly destroyed by a series of circulating enzymes and membranes generically defined as kininases. One of these kininases cleaves bradykinin at the C-terminal arginine thus forming a des-Arg-BK which acts as B1 receptor agonist.
The activation of bradykinin B1 and B2 receptors induces relaxation of vasal muscles with consequent hypotension, increase in vascular permeability, contraction of smooth muscles of intestine and respiratory tract, stimulation of nociceptive neurons, alteration of ionic epithelial secretion, production of nitroxide and release of cytokines by leukocytes and eicosanoids from different cell types. As a consequence, antagonistic compounds of BK receptors can be considered a novel class of medicaments supposedly active in various disorders. Possible therapeutical applications for said antagonists are inflammatory, allergic and autoimmune disorders, such as asthma and chronic bronchitis (also induced by irritants), allergic, vasomotor and viral rhinitis, obstructive pulmonary disease (COPD), rheumatoid arthritis, chronic inflammatory diseases of the bowel (Crohn's disease and ulcerative colitis), glomerulonephritis, psoriasis, rash, acute and chronic cystitis; degenerative disorders characterized by fibrosis, such as hepatic cirrhosis, glomerulopathies and pulmonary fibrosis, arteriosclerosis; thanks to their analgesic activity, in the treatment of both acute and chronic pain, for example in burns, cephalea, insects bites, chronic pain in cancer patients; in disorders of the cardiovascular apparatus such as septic, allergic and post-traumatic shocks, and hepatic cirrhosis by hepatorenal syndrome; as anticancer and antiangiogenetics; in the treatment of hypotension and of alopecia.
Different peptide and non-peptide antagonists of bradykinin B2 receptor are known in literature. Intellectual Property Publication WO03103671 discloses a large family of compounds with antagonistic activity on bradykinin B2 receptor. The compounds of the present invention, although being included in the general formula of WO03103671, are not described or characterized in said document.